Abstract Ca2+ is a ubiquitous signaling messenger mediating many essential functions such as excitability, exocytosis and transcription. In the airway epithelial cells (AECs) lining the conducting airways of the lung, Ca2+ signals are implicated in numerous cellular functions through effects on enzymatic cascades and transcriptional factors. Ca2+ homeostasis is also closely integrated with other signaling systems including that of reactive oxygen species (ROS), which has many cellular functions of its own and is implicated in allergic lung diseases and injury. We have recently shown that store-operated Ca2+ release-activated Ca2+ (CRAC) channels serve as the main pathway for Ca2+ entry in bronchial epithelial cells and their activation leads to increases in levels of numerous proinflammatory cytokines. However, the broader significance of CRAC channels in AECs for mediating airway inflammation and potential crosstalk with ROS and other signaling pathways mediating inflammation remains unknown. We hypothesize that CRAC channels are a major mechanism for controlling the generation of inflammatory mediators from AECs in response to stimulation of cell surface G-protein coupled receptors such as protease-activated and ATP receptors, and are an essential mediator of pulmonary inflammation in diseases such as asthma. We will address this hypothesis through three specific goals: 1) examine the physiological contributions of CRAC channels for allergen- mediated release of ATP and determine how this release stimulates inflammatory cytokines from AECs, 2) investigate the functional interactions between CRAC channels and mitochondrial ROS signaling and assess the impact of this crosstalk for inflammatory cytokine generation, and 3) evaluate the contribution of CRAC channels for mediating airway inflammation in vivo in a mouse model of house dust mite-induced asthma. Together, these studies will advance our understanding of how CRAC channels regulate cellular Ca2+-dependent signaling pathways to modulate allergen-stimulated inflammatory mediators in the airways, and advance the quest for developing novel treatments for allergic airway diseases.